Cell-specific targeting for delivery of diagnostic or therapeutic agents is a widely researched field and has led to the development of noninvasive diagnostic and/or therapeutic medical applications. In particular in the field of nuclear medicine procedures and treatments, which employ radioisotopes characterized by emission of gamma-rays or beta or alpha particles or Auger electrons, selective localization of these radioactive compounds in targeted cells or tissues is required to achieve either high signal intensity and specificity for visualization (gamma- or positron radiation) of specific tissues, assessing a disease and/or monitoring effects of therapeutic treatments, or to achieve high radiation dose through particle radiation (beta- or alpha-radiation), for delivery of adequate doses of ionizing radiation to a specified diseased site, while preventing damage to healthy tissues.
The folate receptor (FR) is a high-affinity membrane-associated protein, which exhibits limited expression on healthy cells, but is frequently overexpressed on a wide variety of specific cell types, such as epithelial tumor cells (e.g. ovarian, endometrial, breast, colorectal, kidney, lung, nasopharyngeal) and activated (but not resting) macrophages, which are involved in inflammation and autoimmune diseases. This led to the use of folic acid and its derivatives as a targeting agent for the delivery of therapeutic and/or diagnostic agents to these specific cell populations to achieve a selective concentration of pharmaceutical and/or diagnostic agents in these specific cells relative to normal cells. Such folate-conjugates include folate radiopharmaceuticals (Leamon and Low, Drug Discov. Today 2001; 6:44-51; Ke et al., Adv Drug Deliv Rev 2004, 1143-1160, Müller and Schibli, J Nucl Med 2011; 52:1-4; Müller, Curr Pharm Design 2012; 18:1058-1083), folate-conjugates of chemotherapeutic agents (Leamon and Reddy, Adv. Drug Deliv. Rev. 2004; 56:1127-41; Leamon et al, Bioconjugate Chem. 2005; 16:803-11; Vlahov et al. Bioconjug Chem 2012; in press), proteins and protein toxins (Ward et al., J. Drug Target. 2000; 8:119-23; Leamon et al, J. Biol. Chem. 1993; 268:24847-54; Leamon and Low, J. Drug Target. 1994; 2:101-12), antisense oligonucleotides (Li et al, Pharm. Res. 1998; 15:1540-45; Zhao and Lee, Adv. Drug Deliv. Rev. 2004; 56:1193-204), liposomes (Lee and Low, Biochim. Biophys. Acta-Biomembr. 1995; 1233:134-44); Gabizon et al, Adv. Drug Deliv. Rev. 2004; 56:1177-92), hapten molecules (Paulos et al, Adv. Drug Deliv. Rev. 2004; 56:1205-17); MRI contrast agents (Konda et al, Magn. Reson. Mat. Phys. Biol. Med. 2001; 12:104-13) etc.
Known folate radiopharmaceuticals include for example conjugates with 125I-labeled histamine (U.S. Pat. No. 4,136,159), with small metal-chelates such as deferoxamine (U.S. Pat. No. 5,688,488), acyclic or cyclic polyaminocarboxylates (e.g. DTPA, DTPA-BMA, DOTA and DO3A; U.S. Pat. No. 6,221,334, Fani et al. Eur J Nucl Med Mol Imaging 2011; 38: 108-119; Müller et al. Nucl Med Biol 2011; 38: 715-723), bisaminothiol (U.S. Pat. No. 5,919,934), 6-hydrazinonicotinamido-hydrazido (Shuang Liu, Topics in Current Chemistry, vol 252 (2005), Springer Berlin/Heidelberg), and ethylenedicysteine (U.S. Pat. No. 7,067,111), and small peptides (U.S. Pat. No. 7,128,893).
However, there is still a need for alternative, highly selective radionuclide conjugates, which can be synthesized easily and which exhibit optimal target (i.e. tumor cell, activated macrophage, etc.) to non-target tissue ratios and are eliminated through the kidneys, for use as tumor imaging agents in highly selective and non-invasive procedures permitting early detection and treatment of tumor cells, activated macrophages (and other targeted cells exhibiting high FR expression, not yet identified).
Applicants have now found novel trifunctional folate-conjugates that are able to overcome the drawbacks of known conjugates and meet the current needs by showing several advantages, such as stable complex formation, improved biodistribution and increased target tissue uptake. These novel trifunctional folate-conjugates comprise a folate, an albumin binder and a radionuclide-based therapeutic moiety or diagnostic moiety, e.g. a moiety suitable for diagnostic imaging or radiotherapeutic applications.